The association of diabetes and cognitive decline may indicate that high sugar level might be a risk factor for Alzheimer's disease. A collective term 'diabetes associated cognitive decline' (DACD) has been coined for the patients with type 2 diabetes mellitus showing decline in their cognitive function, especially weak episodic memory, cognitive inflexibility and poor psychomotor performance leading towards Alzheimer's disease. However, at present, no specific treatment exists for the prevention and/or treatment of DACD. Genistein, an isoflavone phytoestrogen, reveals neuroprotective effects in many experimental murine models, though its role on DACD with probable mechanistic approach has still been scope for research. The motive behind the present study is to investigate the outcome of genistein treatment against DACD in streptozotocin-induced diabetic mice with Morris water maze paradigm followed by open field trial to rule out the possibility of impairment in locomotor performance. Chronic (30 days) genistein treatment (2.5, 5.0 and 10.0 mg/kg, i.p. once daily) in diabetic mice significantly lowered hyperglycemia, recovered cognitive performance by affecting acetylcholinesterase activity and oxidative stress and ameliorated neuro-inflammatory condition by varying TNF-α, IL-1β and nitrite levels as impaired in diabetic mice. Thirty days treatment with vitamin C or metformin also improved diabetes-induced memory impairment and significantly dragged these biochemical parameters towards respective controls. Locomotor performance was not influenced by diabetic condition or any associated treatment. It is concluded that genistein supplementation might be a prospective therapeutic approach for the treatment and/or avoidance of diabetic linked learning and memory dysfunction.